Process for piperidine derivatives

ABSTRACT

The present invention is related to a novel process for preparing certain piperidine derivatives which are useful as antihistamines, antiallergy agents and bronchodilators.

This is a division of application Ser. No. 08/369,234, filed Jan. 6,1995, which is a continuation-in-part of Ser. No. 08/152,606, filed Nov.15, 1993, now abandoned; which is a continuation-in-part of Ser. No.08/099,773, filed Jul. 30, 1993, now abandoned; which is a continuationof Ser. No. 08/017,251, filed Feb. 25, 1993, now abandoned; which is acontinuation-in-part of Ser. No. 08/009,370, filed Jan. 26, 1993, nowabandoned; which is a continuation of Ser. No. 07/867,261, filed Apr.10, 1992, now abandoned.

BACKGROUND OF THE INVENTION

The present invention is related to a novel process for preparingcertain piperidine derivatives which are useful as antihistamines,antiallergy agents and bronchodilators [U.S. Pat. No. 4,254,129, Mar. 3,1981, U.S. Pat. No. 4,254,130, Mar. 3, 1981 and U.S. Pat. No. 4,285,958,Apr. 25, 1981].

These piperidine derivatives can be described by the following formulas:##STR1## wherein

R₁ represents hydrogen or hydroxy;

R₂ represents hydrogen; or

R₁ and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂ ;

n is an integer of from 1 to 5;

R₃ is --CH₂ OH, --COOH or --COOalkyl wherein the alkyl moiety has from 1to 6 carbon atoms and is straight or branched;

each of A is hydrogen or hydroxy; and

pharmaceutically acceptable salts, hydrates and individual opticalisomers thereof.

The novel process for preparing the piperidine derivatives of formula(I) and formula (II) of the present invention offers high yields andease of purification.

SUMMARY OF THE INVENTION

The present invention provides a novel process for preparing thepiperidine derivatives of formula (I) and formula (II) ##STR2## wherein

R₁ represents hydrogen or hydroxy;

R₂ represents hydrogen; or

R₁ and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂ ;

n is an integer of from 1 to 5;

R₃ is --CH₂ OH, --COOH or --COOalkyl wherein the alkyl moiety has from 1to 6 carbon atoms and is straight or branched;

each of A is hydrogen or hydroxy; and

pharmaceutically acceptable salts, hydrates and individual opticalisomers thereof comprising the steps of:

(a) reacting a benzeneacetic acid compound of the formula ##STR3##wherein A is as defined above and R is hydrogen or C₁ -C₆ alkyl with asuitable reducing agent to give a phenethyl alcohol;

(b) reacting the phenethyl alcohol with a ω-halo compound of the formula##STR4## wherein B is halo or hydroxy, Hal represents Cl, Br or I and nis as defined above, in the presence of a suitable Lewis acid to producea ω-halo hydroxyethylphenylketone; and

(c) reacting the ω-halo hydroxyethylphenylketone with a piperidinecompound of the formula ##STR5## wherein R₁ and R₂ are as defined abovein the presence of a suitable non-nucleophilic base to produce apiperidine hydroxyethylphenylketone derivative of formula (II) whereinR₃ is --CH₂ OH;

(d) optionally reacting the piperidine hydroxyethyiphenylketonederivative of formula (II) wherein R₃ is --CH₂ OH with a suitableoxidizing agent to produce a piperidine carboxyphenylketone derivativeof formula (II) wherein R₃ is --COOH;

(e) optionally reacting the piperidine carboxyphenylketone derivative offormula (II) wherein R₃ is --COOH to produce a piperidinecarboxyphenylketone ester derivative of formula (II) wherein R₃ is--COOalkyl.

(f) optionally reacting the piperidine carboxyphenylketone derivative offormula (II) wherein R₃ is --COOH or the piperidine carboxyphenylketoneester derivative of formula (II) wherein R₃ is --COOalkyl with asuitable reducing agent to produce a piperidine carboxyphenylalcoholderivative of formula (I) wherein R₃ is --COOH or the piperidinecarboxyphenylalcohol ester of formula (I) wherein R₃ is --COOalkyl;

(g) optionally reacting the piperidine carboxyphenylalcohol derivativeof formula (I) wherein R₃ is --COOH to produce a piperidinecarboxyphenylalcohol ester derivative of formula (I) wherein R₃ is--COOalkyl; and

(h) optionally reacting the piperidine hydroxyethylphenylketonederivative of formula (II) wherein R₃ is --CH₂ OH, the piperidinecarboxyphenylketone derivative of formula (II) wherein R₃ is --COOH, thepiperidine carboxyphenylketone ester derivative of formula (II) whereinR₃ is --COOalkyl, the piperidine carboxyphenylalcohol derivative offormula (I) wherein R₃ is --COOH or the piperidine carboxyphenylalcoholester of formula (i) wherein R₃ is --COOalkyl with an appropriatedeprotecting reagent,

with the proviso that each of the hydroxy groups present in thecompounds described in steps a-g are optionally protected orunprotected.

Alternatively, the present invention provides a novel process forpreparing the piperidine derivatives of formula (I) comprising the stepsof:

(a) reacting the ω-halo hydroxyethylphenylketone with a suitablereducing agent to produce a ω-halo hydroxyethylphenylalcohol;

(b) reacting the ω-halo hydroxyethylphenylalcohol with a piperidinecompound of the formula ##STR6## wherein R₁ and R₂ are as defined above,in the presence of a suitable non-nucleophilic base to produce apiperidine hydroxyethylphenylalcohol derivative of formula (I) whereinR₃ is --CH₂ OH;

(c) optionally reacting the piperidine hydroxyethylphenylalcoholderivative of formula (i) wherein R₃ is --CH₂ OH with a suitableoxidizing agent to produce a piperidine carboxyphenylalcohol derivativeof formula (I) wherein R₃ is --COOH; and

(d) optionally reacting the piperidine carboxyphenylalcohol derivativeof formula (I) wherein R₃ is --COOH to produce the piperidinecarboxyphenylalcohol ester derivative of formula (I) wherein R₃ is--COOalkyl.

(e) optionally reacting the piperidine hydroxyethylphenylalcoholderivative of formula (I) wherein R₃ is --CH₂ OH, the piperidinecarboxyphenylalcohol derivative of formula (I) wherein R₃ is --COOH orthe piperidine carboxyphenylalcohol ester derivative of formula (I)wherein R₃ is --COOalkyl with an appropriate deprotecting reagent,

with the proviso that each of the hydroxy groups present in thecompounds described in steps a-d are optionally protected orunprotected.

In addition, the present invention provides a novel process forpreparing the piperidine derivatives of formula (I) comprising the stepsof:

(a) reacting the piperidine hydroxyethylphenylketone derivative offormula (II) wherein R₃ is --CH₂ OH with a suitable reducing agent toproduce a piperidine hydroxyethylphenylalcohol derivative of formula (I)wherein R₃ is --CH₂ OH;

(b) optionally reacting the piperidine hydroxyethylphenylalcoholderivative of formula (I) wherein R₃ is --CH₂ OH with a suitableoxidizing agent to produce a piperidine carboxyphenylalcohol derivativeof formula (I) wherein R₃ is --COOH; and

(c) optionally reacting the piperidine carboxyphenylatcohol derivativeof formula (I) wherein R₃ is --COOH to produce the piperidinecarboxyphenylalcohol ester derivative of formula (I) wherein R₃ is--COOalkyl.

(d) optionally reacting the piperidine hydroxyethylphenylketonederivative of formula (II) wherein R₃ is --CH₂ OH, the piperidinehydroxyethylphenylalcohol derivative of formula (I) wherein R₃ is --CH₂OH, the piperidine carboxyphenylalcohol derivative of formula (I)wherein R₃ is --COOH or the piperidine carboxyphenylalcohol esterderivative of formula (I) wherein R₃ is --COOalkyl with an appropriatedeprotecting reagent with the proviso that each of the hydroxy groupspresent in the compounds described in steps a-c are optionally protectedor unprotected.

As used herein, straight or branched alkyl groups having from 1 to 6carbon atoms as referred to herein are methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl andn-hexyl.

The piperidine derivatives of the formula (I) and formula (II) can formpharmaceutically acceptable salts. Pharmaceutically acceptable acidaddition salts of the compounds of this invention are those of anysuitable inorganic or organic acid. Suitable inorganic acids are, forexample, hydrochloric, hydrobromic, sulfuric, and phosphoric acids.Suitable organic acids include carboxylic acids, such as, acetic,propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic,tartaric, citric, cyclamic, ascorbic, maleic, hydroxymaleic, anddihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic,4-hydroxybenzoic, anthranillic, cinnamic, salicyclic, 4-aminosalicyclic,2-phenoxybenzoic, 2-acetoxybenzoic, and mandelic acid, sulfonic acids,such as, methanesulfonic, ethanesulfonic and β-hydroxyethanesulfonicacid. Non-toxic salts of the compounds of the above-identified formulaformed with inorganic or organic bases are also included within thescope of this invention and include, for example, those of alkalimetals, such as, sodium, potassium and lithium, alkaline earth metals,for example, calcium and magnesium, light metals of group IIIA, forexample, aluminum, organic amines, such as, primary, secondary ortertiary amines, for example, cyclohexylamine, ethylamine, pyridine,methylaminoethanol and piperazine. The salts are prepared byconventional means as, for example, by treating a piperidine derivativeof formula (I) or formula (II) with an appropriate acid or base.

As used herein, the term "hydrate" refers to a combination of water witha compound of formula (I) or (II) wherein the water retains itsmolecular state as water and is either absorbed, adsorbed or containedwithin a crystal latice of the substrate molecule of formula (I) or(II).

As used herein, the term "adsorped" refers to the physical state whereinthe water molecule in the hydrated, pharmaceutically acceptable acidaddition salts of piperidine derivatives of the formula (I) and (II) isdistributed over the surface of the solid hydrated, pharmaceuticallyacceptable acid addition salts of piperidine derivatives of the formula(I) and (II).

As used herein, the term "absorbed" refers to the physical state whereinthe water molecule in the hydrated, pharmaceutically acceptable acidaddition salts of piperidine derivatives of the formula (I) and (II) isdistributed throughout the body of the solid hydrated, pharmaceuticallyacceptable acid addition salts of piperidine derivatives of the formula(I) and (II).

Hydrated, pharmaceutically acceptable acid addition salts of thecompounds of formula (I) and (II) are those hydrates ranging fromessentially 0.10 to 5 molecules of water per molecule of substrate saltof formula (I) or (II).

The novel process for preparing the piperidine derivatives of formula(I) and formula (II) is outlined in Scheme A. In Scheme A, allsubstituents are as previously defined unless otherwise indicated.##STR7## A'=hydrogen, protected hydroxy or hydroxy B=Halo or OH

D=hydrogen or a suitable protecting group

R₁ ' and R₂ '=hydrogen, protected hydroxy, hydroxy or taken together toform a second bond between the carbon atoms bearing R₁ ' and R₂ '

R=C₁ -C₆ alkyl or hydrogen

Scheme A provides a general synthetic procedure for preparing thepiperidine derivatives of formula (I) and formula (II).

In step a, the carboxy functionality of an appropriate benzeneaceticacid compound of structure (1), wherein R is hydrogen or C₁ -C₆ alkyl,is reduced to give the corresponding phenethyl alcohol of structure (2),wherein D is hydrogen.

For example, reduction of the appropriate benzeneacetic acid ofstructure (1), wherein R is hydrogen, using, for example, sodiumbis(2-methoxyethoxy)aluminum hydride, lithium aluminum hydride, diboraneor aluminum hydride with diborane being preferred. Reduction of theappropriate benzeneactic acid of structure (1), wherein R is C₁ -C₆alkyl, using, for example, lithium aluminum hydride, lithiumborohydride, sodium bis(2-methoxyethoxy)aluminum hydride, aluminumhydride, lithium triethylborohydride and lithiumtri-sec-butylborohydride with lithium aluminum hydride being preferred.Suitable solvents are ethers, for example, diethyl ether,tetrahydrofuran or dioxane. These reduction reactions are carried out attemperatures ranging from about 0° C. to the reflux temperature of thesolvent, and the reaction time varies from about 1/2 hour to 8 hours.

The starting benzeneacetic acid compounds of structure (1) are known inthe art of are prepared by procedures well known in the art. Forexample, the benzeneacetic acid compound of structure (1) wherein R isC₁ -C₆ alkyl and A' is hydroxy may be prepared by treating a hotsolution of 1 equivalent of an appropriate straight or branched alkylC₁₋₆ ester of 3-trifluoroacetoxyphenylacetic acid in dimethoxyethanewith a base, such as, sodium hydride under a nitrogen atmospherefollowed by the addition of 2.1 equivalents of methyliodide indimethoxyethane to the mixture over about a 20 minute period. Themixture is refluxed for about 3 hours then concentrated to remove mostof the solvent after which diethyl ether, then water are addedcautiously. The organic layer is separated, extracted with ether, driedover magnesium sulfate and distilled to give the appropriate ester ofthe benzeneacetic acid compound of structure (1) wherein A' is atrifluoroacetoxy protected hydroxy and R is C₁ -C₆ alkyl. To a solutionof the methylated ester in 50% alcohol/water is added 3× molar amount ofpotassium carbonate. The solution is stirred at about 25° C. for about 8hours then concentrated to a semisolid at reduced pressure at about 50°C. and upon cooling water is added and the mixture is neutralized withdilute hydrochloric acid then extracted with ether. The ether extract isdried over magnesium sulfate, filtered and concentrated to give theappropriate ester of the benzeneacetic acid compound of structure (1)wherein A' is hydroxy and R is C₁ -C₆ alkyl. The esters of thebenzeneacetic acid compounds of structure (1) wherein A' is atrifluoroacetoxy protected hydroxy and R is C₁ -C₆ alkyl are known inthe art, for example, from ethyl m-hydroxyphenylacetate by treatmentwith trifluoroacetic anhydride.

Alternatively, the phenethyl alcohol compounds of structure (2) may beprepared by Friedel-Crafts acylation of an appropriate benzene compoundwith a suitable protected 2-methyl-2-propenyl alcohol compound. Forexample, the phenethyl alcohol compound of structure (2) wherein A' ishydrogen, hydroxy or a suitably protected hydroxy may be prepared byreacting an appropriate 2-methyl-2-propenyl alcohol compound with anappropriate benzene compound in the presence of AlCl₃.

In step b, the appropriate phenethyl alcohol of structure (2), whereinA' is hydrogen, hydroxy or a suitably protected hydroxy, is acylatedwith the ω-halo compound of structure (3) wherein B is halo underFreidel-Crafts conditions to give the corresponding ω-halohydroxyethylphenylketone of structure (4) wherein A' is described asabove.

For example, the ω-halo hydroxyethylphenylketone of structure (4),wherein A' is hydrogen, hydroxy or a protected hydroxy, may be preparedby reacting an appropriate phenyethyl alcohol of structure (2), whereinA' is hydrogen, hydroxy or a protected hydroxy, with a appropriateω-halo compound of structure (3) wherein B is halo, which are known inthe art or are prepared by procedures well known in the art, under thegeneral conditions of a Friedel-Crafts acylation using a suitable Lewisacid. The reaction is carried out in a solvent, such as carbondisulfide, methylene chloride, tetrachloroethane or nitrobenzene withmethylene chloride being the preferred solvent. The reaction time variesfrom about 1/2 hour to 8 hours, preferably 1 to 5 hours and the reactiontemperature varies from about 0° C. to 25° C. The ω-halohydroxyethylphenylketone of structure (4) wherein A' is hydrogen,hydroxy or a protected hydroxy is recovered from the reaction zone by anaqueous quench followed by extraction as is known in the art. The ω-halohydroxyethylphenylketone of structure (4) wherein A' is hydrogen,hydroxy or a protected hydroxy may be purified by procedures well knownin the art, such as crystallization.

Alternatively, the appropriate phenethyl alcohol of structure (2)wherein A' is hydroxy may be acylated with the ω-halo compound ofstructure (3) wherein B is hydroxy in the presence of a Lewis acid togive the corresponding halo hydroxyethylphenylketone of structure (4) asdescribed in Arch. Pharm. 306, 807 1973. In general, an appropriatephenethyl alcohol of structure (2), wherein A' is hydroxy, and theω-halo compound of structure (3), wherein B is hydroxy, are meltedtogether at about 50° C., then cooled to about 10° C. after which aLewis acid is added in an amount about 2.2 times the molar amount of theappropriate phenethyl alcohol of structure (2), wherein A' is hydroxy,employed. The mixture is heated at about 70° C. for about 2 hours afterwhich a 30% sodium acetate solution is added and extracted with ether.The organic layer is dried and the solvent evaporated to give the ω-halohydroxyethylphenylketone of structure (4) wherein A' is hydroxy. Theω-halo hydroxyethylphenylketone of structure (4) may be purified byprocedures well known in the art, such as crystallization.

Suitable Lewis acids for the acylation reaction described in step b arewell known and appreciated in the art. Examples of suitable Lewis acidsare boron trichloride, aluminum chloride, titanium tetrachloride, borontrifluoride, tin tetrachloride and zinc chloride. The selection andutilization of suitable Lewis acids for the acylation reaction of step bis well known and appreciated by one of ordinary skill in the art.

The starting ω-halo compounds of (3) are commercially available ofeasily prepared by generally known methods.

While not necessary for utilization in the acylation reaction of step b,the hydroxyethyl functionality of those phenethyl alcohols of structure(2) may be protected with a suitable protecting group. The selection andutilization of suitable protecting groups for the phenethyl alcohols ofstructure (2) is well known by one of ordinary skill in the art and isdescribed in "Protective Groups in Organic Syntheses", Theodora W.Greene, Wiley (1981). For example, suitable protecting groups for thehydroxyethyl functionality include ethers such as tetrahydrothiopyranyl,tetrahydrothiofuranyl, 2-(phenylselenyl)ethyl ether, o-nitrobenzylether, trimethylsilyl ether, isopropyldimethylsilyl ether,t-butyldimethylsilyl ether, t-butyldiphenylsilyl ether, tribenzylsilylether, triisopropylsilyl ether; and esters, such as acetate ester,isobutyrate ester, pivaloate ester, adamantoate ester, benzoate ester,2,4,6-trimethylbenzoate (mesitoate) ester, methyl carbonate,p-nitrophenyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonateand N-phenylcarbamate, with acetoxy being preferred.

For those ω-halo hydroxyethylphenylketone of structure (4), wherein A'is hydrogen, hydroxy or a protected hydroxy and D is hydrogen, theFriedel-Crafts acylation may result in acylation of the hydroxyethylfunctionality and will require deprotection prior to the oxidationreaction described in optional step d. Suitable deprotecting agents andmethods are described in optional step d, infra.

While also not necessary for utilization in the acylation reaction ofstep b, the phenol functionality of those phenethyl alcohols ofstructure (2), wherein A' is hydroxy may be protected with a suitableprotecting group. For example, suitable protecting groups for thephenolic hydroxy include methyl ether, 2-methoxyethoxymethyl ether(MEM), cyclohexyl ether, o-nitrobenzyl ether, 9-anthryl ether,t-butyldimethylsilyl ether, acetate, benzoate, methyl carbamate, benzylcarbamate, aryl pivaloate and aryl methanesulfonate.

In step c, the ω-halo functionality of the appropriate ω-halohydroxyethylphenylketone of structure (4) is alkylated with theappropriate piperidine compound of structure (5) to give thecorresponding piperidine hydroxyethylphenylketone derivative of formula(II) wherein R₃ is --CH₂ OH.

For example, the alkylation reaction is carried out in a suitablesolvent preferably in the present of a base and optionally in thepresence of a catalytic amount of an iodide source, such as potassium orsodium iodide, for about 4 to 120 hours and at temperatures of about 70°C. to the reflux temperature of the solvent. Suitable solvent for thealkylation reaction include alcohol solvents such as, methanol, ethanol,isopropyl alcohol, or n-butanol; ketone solvents, such as, methylisobutyl ketone; hydrocarbon solvents, such as, benzene, toluene orxylene; halogenated hydrocarbons, such as, chlorobenzene or methylenechloride or dimethylformamide. Suitable bases for the alkylationreaction include inorganic bases, for example, sodium bicarbonate,potassium carbonate, or potassium bicarbonate or organic bases, such as,a trialkylamine, for example, triethylamine or pyridine, or an excess ofan appropriate piperidine compound of structure (5) may be used.

For those piperidine compounds of structure (5), wherein R₁ is hydroxy,it is preferred that R₁ be unprotected for utilization in the alkyationreaction of step c, but those hydroxy functionalities present in thepiperidine compounds of structure (5), wherein R₁ is hydroxy may beprotected with a suitable protecting group. The selection andutilization of suitable protecting groups for the piperidine compoundsof structure (5), wherein R₁ is hydroxy is well known by one of ordinaryskill in the art and is described in "Protective Groups in OrganicSyntheses", Theodora W. Greene, Wiley (1981). For example, suitableprotecting groups for those hydroxy functionalities present includeethers such as tetrahydrothiopyranyl, tetrahydrothiofuranyl,2-(phenylselenyl)ethyl ether, o-nitrobenzyl ether, trimethylsilyl ether,isopropyldimethylsilyl ether, t-butyldimethylsilyl ether,t-butyldiphenylsilyl ether, tribenzylsilyl ether, triisopropylsilylether; and esters, such as acetate ester, isobutyrate ester, pivaloateester, adamantoate ester, benzoate ester, 2,4,6-trimethylbenzoate(mesitoate) ester, methyl carbonate, p-nitrophenyl carbonate,p-nitrobenzyl carbonate, S-benzyl thiocarbonate and N-phenylcarbamate.

The piperidine compounds of structure (5) wherein R₁ and R₂ are hydrogenand where R₁ is hydroxy and R₂ is hydrogen are readily available to oneor ordinary skill in the art. The piperidine compounds of structure (5)wherein R₁ and R₂ form a second bond between the carbon atoms bearing R₁and R₂ may be prepared by dehydration of the corresponding compoundwherein R₁ is hydroxy by procedures generally known in the art.

In optional step d, the hydroxyethyl functionality of the appropriatepiperidine hydroxyethylphenylketone derivative of formula (II) whereinR₃ is --CH₂ OH is oxidized to give the corresponding piperidinecarboxyphenylketone derivative of formula (II) wherein R₃ is COOH.

For example, oxidation of the appropriate piperidinehydroxyethylphenylketone derivative of formula (II) wherein R₃ is --CH₂OH may be achieved using a variety of oxidizing agents and methods.

One such method involves a two-step procedure in which the hydroxyethylfunctionality of the appropriate piperidine hydroxyethylphenylketonederivative of formula (II) wherein R₃ is --CH₂ OH is first oxidized tothe corresponding aldehyde functionality using, for example, SwernOxidation conditions (dimethyl sulfoxide, oxyalyl chloride andtriethylamine), as is known in the art. The Swern Oxidation is carriedout in suitable aprotic organic solvents such as methylene chloride attemperatures ranging from about -78° C. to room temperature, and thereaction time varies from about 1/2 hour to 8 hours. Other suitablereagents for the oxidation of the hydroxyethyl functionality of theappropriate piperidine hydroxyethylphenylketone derivative of formula(II) wherein R₃ is --CH₂ OH to the corresponding aldehyde functionalityare Dess-Martin reagent, chromium (IV) oxide, nickel peroxide, sodiumdichromate, potassium dichromate, t-butyl chromate, silver oxide,argentic picolinate manganese dioxide lead tetraacetate,dicyclohexylcarbodiimide, 2,3-dichloro-5,6-dicyanoquinone,tetrachloro-1,2-benzoquinone, 2,2,6,6-tetramethylpiperidinyl-1-oxy(TEMPO) or quinolinium chlorochromate.

Alternatively, an intermediate aldehyde compound may be prepared byadministering terfenadine to human subjects, collecting the urine,basifying with a suitable base, such as sodium hydroxide and extractinginto an organic solvent, such as ethyl acetate. After evaporation of theorganic solvent and dissolving the residue in a suitable solvent such asmethanol/water, the intermediate aldehyde compound may be purified byHPLC using, for example, a Spherisorb 5 micrometer CN, 25 cm×4.6 mm IDcolumn; acetonitrile/0.05 M ammonium acetate, pH 4.5 (40/60, v/v) mobilephase; and 1.2 mL/min flow rate.

The intermediate aldehyde compound is then oxidized further to give thecorresponding piperidine carboxyphenylketone derivative of formula (II)wherein R₃ is --COOH using, for example, potassium permanganate. Thepotassium permanganate oxidation is carried out in a suitable acidicmedium such as hydrochloric acid/acetone at a temperature ranging fromabout 0° C. to room temperature and the reaction time varies from about1/2 hour to 8 hours. Other suitable reagents for the oxidation of theintermediate aldehyde to the corresponding piperidinecarboxyphenylketone derivative of formula (II) wherein R₃ is --COOH arechromium (IV) oxide, silver (I) oxide, silver oxide, argenticpicolinate, peroxide, nitric acid, m-chloroperbenzoic acid and peraceticacid.

Another method involves a one-step procedure in which the hydroxyethylfunctionality of the appropriate piperidine hydroxyethylphenylketonederivative of formula (II) wherein R₃ is --CH₂ OH is oxidized directlyto the carboxy functionality to give the corresponding piperidinecarboxyphenylketone derivative of formula (II) wherein R₃ is --COOH.Oxidizing reagents suitable for direct, one-step oxidation of thehydroxyethyl functionality to the carboxy functionality include, forexample, chromaium (IV) oxide, potassium permanganate, nitric acid,nitrogen dioxide, ruthenium (VIII) oxide, nickel peroxide, silver oxide,t-butyl chromate and xenic acid.

Oxidation using Swern Oxidation conditions, nickel peroxide, chromium(IV) oxide, silver oxide, sodium dichromate, potassium dichromate,manganese dioxide, 2,3-dichloro-5,6-dicyanoquinone andtetrachloro-1,2-benzoquinone is preferred for those piperidinehydroxyethylphenylketone derivatives of formula (II) wherein R₃ is --CH₂OH wherein R₁ and R₂ taken together form a second bond between thecarbon atoms bearing R₁ and R₂.

As one skilled in the art would appreciate, those piperidinehydroxyethylphenylketone derivatives of formula (II) wherein R₃ is --CH₂OH wherein the hydroxyethyl functionality is protected must be reactedwith an appropriate deprotecting reagent prior to the oxidation reactiondescribed in step d. The selection and utilization of appropriatedeprotecting reagents is well known by one of ordinary skill in the artand is described in "Protective Groups in Organic Syntheses", TheodoraW. Greene, Wiley (1981). Examples of appropriate deprotecting reagentsare mineral acids, strong organic acids, Lewis acids, aqueous mineralbases, catalytic hydrogenation and the like. For example, cleavage of anacetate ester protecting group on the hydroxyethyl functionality of thepiperidine hydroxyethylphenylketone derivatives of formula (II) whereinR₃ is --CH₂ OH can be achieved by using a base, such as sodium methoxidein methanol as is known in the art. Other methods known in the art foracetate ester cleavage include potassium carbonate in methanol,methanolic ammonia, sodium hydroxide/pyridine in methanol and potassiumcyanide in ethanol.

In optional step e, the ketone functionality of the appropriatepiperidine carboxyphenylketone derivatives of formula (II) wherein R₃ is--CH₂ OD or --COOH is reduced to give the corresponding piperidinecarboxyphenylalcohol derivatives of formula (I) wherein R₃ is --CH₂ ODor --COOH. For example, reduction of the appropriate piperidinecarboxyphenylketone derivatives of formula (II) wherein R₃ is --CH₂ ODor --COOH, using, for example, sodium borohydride, potassiumborohydride, sodium cyanoborohydride, or tetramethylammonium borohydrideis carried out in lower alcohol solvents, such as, methanol, ethanol,isopropyl alcohol or n-butanol at temperatures ranging from about 0° C.to the reflux temperature of the solvent, and the reaction time variesfrom about 1/2 hour to 8 hours. Other suitable reducing agents are, forexample, lithium tri-tert-butylaluminohydride and diisobutylaluminumhydride. These reduction reactions are carried out in suitable solventsdiethyl ether, tetrahydrofuran or dioxane at temperatures ranging fromabout 0° C. to the reflux temperature of the solvent, and the reactiontime varies from about 1/2 hour to 8 hours.

Catalytic reduction may also be employed in the preparation ofappropriate piperidine carboxyphenylalcohol derivatives of formula (I)wherein R₃ is --CE₂ OD or --COOH from an appropriate piperidinecarboxyphenylketone derivatives of formula (II) wherein R₃ is --CH₂ ODor --COOH, using, for example, Raney nickel, palladium, platinum orrhodium catalysts in lower alcohol solvents, such as, methanol, ethanol,isopropyl alcohol or n-butanol or acetic acid or their aqueous mixtures,or by the use of aluminum isopropoxide in isopropyl alcohol.

Reduction using sodium borohydride or potassium borohydride is preferredover catalytic reduction for those piperidine carboxyphenylketonederivatives of formula (II) wherein R₃ is --CH₂ OD or --COOH wherein R₁and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂.

In addition, a chiral reduction of the appropriate piperidinecarboxyphenylketone derivatives of formula (II) wherein R₃ is --CH₂ ODor --COOH, using, for example, (+)-B-chlorodiisopinocamphenylboranegives the corresponding (R)-piperidine carboxyphenylalcohol derivativesof formula (I) wherein R₃ is --CH₂ OD or --COOH and(-)-B-chlorodiisopinocamphenylborane gives the corresponding(S)-piperidine carboxyphenylalcohol derivatives of formula (I) whereinR₃ is --CH₂ OD or --COOH. Other suitable chiral reducing agents are, (R)and (S)-oxazaborolidine/BH₃, potassium9-O-(1,2:5,6-di-O-isopropylidine-α-D-glucofuransoyl)-9-boratabicyclo[3.3.1]nonane,(R) and (S)-B-3-pinanyl-9-borabicyclo[3.3.1]nonane, NB-Enantride,Lithium (R)-(+) and (S)-(-)-2,2'-dihydroxy-1,1'-binaphthyl alkoxylaluminum hydride, (R)-(+) and(S)-(-)-2,2'-dihydroxy-6,6'-dimethylbiphenyl borane-amine complex,tris[[(1S,2S,5R)-2-isopropyl-5-methyl-cyclohex-1-yl]methyl]aluminum,[[(1R,3R)-2,2-dimethylbicyclo[2.2.1]hept-3-yl]methyl]beryllium chloride,(R)-BINAP-ruthenium complex/H₂ and6,6'-bis(diphenylphosphino)-3,3'-dimethoxy-2,2',4,4'-tetramethyl-1,1'-biphenyl.

As one skilled in the art would appreciate, the carboxy functionalitiesof the piperidine carboxyphenylketone derivatives of formula (II)wherein R₃ is --COOH and piperidine carboxyphenylalcohol derivatives offormula (I) wherein R₃ is --COOH may be esterified by techniques andprocedures well known and appreciated by one of ordinary skill in theart to give the corresponding piperidine carboxyphenylketone esterderivatives of formula (II) wherein R₃ is --COOalkyl and piperidinecarboxyphenylalcohol ester derivatives of formula (I) wherein R₃ is--COOalkyl.

For example, one such method involves reacting an appropriate piperidinecarboxyphenylketone derivative of formula (II) wherein R₃ is --COOH withan excess of an appropriate HOalkyl wherein the alkyl moiety has from 1to 6 carbon atoms and is straight or branched in the presence of a smallamount of mineral acid, e.g. sulfuric acid at reflux. Another suitablemethod involves reacting an appropriate piperidine carboxyphenylketonederivative of formula (II) wherein R₃ is --COOH or piperidinecarboxyphenylalcohol derivative of formula (I) wherein R₃ is --COOH withan excess of diazomethane in a suitable solvent such as ether at roomtemperature to give the methyl ester. In addition, the piperidinecarboxyphenylketone ester derivatives of formula (II) wherein R₃ is--COOalkyl or piperidine carboxyphenylalcohol ester derivatives offormula (I) wherein R₃ is --COOalkyl may also be prepared by reacting anappropriate piperidine carboxyphenylketone derivatives of formula (II)wherein R₃ is --COOH or piperidine carboxyphenylalcohol derivatives offormula (I) wherein R₃ is --COOH with an excess of 2,2-dimethoxypropanein a suitable solvent such as methanol at 0° C. to room temperature togive the methyl ester. Another suitable method involves first reactingan appropriate piperidine carboxyphenylketone derivatives of formula(II) wherein R₃ is --COOH with thionyl chloride in a suitable solventsuch as methylene chloride to give an intermediate acid chloride,followed by addition of a suitable alcohol of the formula HOalkylwherein the alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched.

As one skilled in the art would appreciate, the reduction of the ketonefunctionality of the appropriate piperidine carboxyphenylketonederivatives of formula (II) wherein R₃ is --COOH described in optionalstep e can be conducted on the ω-halo hydroxyethylphenylketone ofstructure (4) or piperidine hydroxyethylphenylketone derivatives offormula (II) wherein R₃ is --CH₂ OH.

For example, reduction of an appropriate ω-halo hydroxyethylphenylketoneof structure (4) using the techniques and methods described previouslyin step e gives the corresponding e-halo hydroxyethylphenylalcohol. Theresulting benzylic alcohol functionality may be optionally protectedusing the protecting groups described previously for hydroxyethyl instep b. The ω-halo hydroxyethylphenylalcohol so formed is then subjectedto the alkylation reaction with an appropriate piperidine compound ofstructure (5) described previously in step c to give the correspondingpiperidine hydroxyethylphenylalcohol derivative of formula (I) whereinR₃ is protected or unprotected --CH₂ OH. The appropriate piperidinehydroxyethylphenylalcohol derivative of formula (I) wherein R₃ is --CH₂OH is then subjected to the oxidation reaction described previously instep d using a selective oxidizing agent such as2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO) or quinoliniumchlorochromate to give the intermediate aldehyde followed by oxidationwith silver oxide to give the corresponding piperidinecarboxyphenylalcohol derivative of formula (I) wherein R₃ is --COOH.Reduction of an appropriate piperidine hydroxyethylphenylketonederivative of formula (II) wherein R₃ is protected or unprotected --CH₂OH using the techniques and methods described previously in step e givesthe corresponding piperidine hydroxyethylphenylalcohol derivative offormula (I) wherein R₃ is --CH₂ OH which is then subjected to theoxidation reaction described previously in step d using a selectiveoxidizing agent such as 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO) orquinolinium chlorochromate to give the intermediate aldehyde followed byoxidation with silver oxide to give the corresponding piperidinecarboxyphenylalcohol derivative of formula wherein R₃ is --COOH.

As one skilled in the art would appreciate, the benzeneacetic acidcompounds of structure (1), the phenethyl alcohols of structure (2), theω-halo hydroxyethylphenylketones of structure (4), piperidine compoundsof structure (5), piperidine hydroxyethylphenylketone derivatives offormula (II) wherein R₃ is --CH₂ OH, the piperidine carboxyphenylketonederivatives of formula (II) wherein R₃ is --COOH, the piperidinecarboxyphenylketone ester derivatives of formula (II) wherein R₃ is--COOalkyl, the piperidine hydroxyethylphenylalcohol derivatives offormula (I) wherein R₃ is --CH₂ OH, the piperidine carboxyphenylalcoholderivatives of formula (I) wherein R₃ is COOH or the piperidinecarboxyphenylalcohol ester derivatives of formula (I) wherein R₃ is--COOalkyl which bear hydroxy or phenolic functionalities may beprotected prior to use in the synthesis depicted in Scheme A usingsuitable protecting groups as described previously in step b.

As one skilled in the art would appreciate, the benzeneactic acids ofstructure (1), the phenethyl alcohols of structure (2), the ω-halohydroxyethylphenylketones of structure (4), piperidine compounds ofstructure (5), piperidine hydroxyethylphenylketone derivatives offormula (II) wherein R₃ is --CH₂ OH, the piperidine carboxyphenylketonederivatives of formula (II) wherein R₃ is --COOH or the piperidinecarboxyphenylketone ester derivatives of formula (II) wherein R₃ is--COOalkyl, the piperidine hydroxyethylphenylalcohol derivatives offormula (I) wherein R₃ is --CH₂ OH, the piperidine carboxyphenylalcoholderivatives of formula (I) wherein R₃ is COOH or the piperidinecarboxyphenylalcohol ester derivatives of formula (I) wherein R₃ isCOOalkyl which bear protected hydroxy or phenolic functionalities may bereacting with prior appropriate deprotecting reagents prior to use inthe synthesis depicted in Scheme A. The selection and utilization ofappropriate deprotecting reagents is well known by one of ordinary skillin the art and is described in "Protective Groups in Organic Syntheses",Theodora W. Greene, Wiley (1981). Examples of appropriate deprotectingreagents are mineral acids, strong organic acids, Lewis acids, aqueousmineral bases, catalytic hydrogenation and the like.

For example, cleavage of an acetate ester protecting group on thehydroxyethyl functionality of any of the ω-halohydroxyethylphenylketones of structure (4), piperidine compounds ofstructure (5), piperidine hydroxyethylphenylketone derivatives offormula (II) wherein R₃ is --CH₂ OH or piperidinehydroxyethylphenylalcohol derivatives of formula (I) wherein R₃ is --CH₂OH can be achieved by using a base, such as sodium methoxide in methanolas is known in the art. Other methods known in the art for acetate estercleavage include potassium carbonate in methanol, methanolic ammonia,sodium hydroxide/pyridine in methanol and potassium cyanide in ethanol.

Cleavage of β-methoxyethoxymethyl (MEM) protecting groups on any ofthose ω-halo hydroxyethylphenylketones of structure (4), piperidinecompounds of structure (5), piperidine hydroxyethylphenylketonederivative of formula (II) wherein R₃ is --CH₂ OH, piperidinecarboxyphenylketone derivative of formula (II) wherein R₃ is --COOH,piperidine carboxyphenylketone ester derivatives of formula (II) whereinR₃ is --COOalkyl, piperidine carboxyphenylalcohol derivatives of formula(I) wherein R₃ is --COOH, piperidine carboxyphenylalcohol esterderivatives of formula (I) wherein R₃ is --COOalkyl or piperidinehydroxyethylphenylalcohol derivatives of formula (I) wherein R₃ is --CH₂OH wherein A is hydroxy, for example, can be achieved by usingtrifluoroacetic acid at room temperature or using 5 to 8 equivalents ofpowdered anhydrous zinc bromide in methylene chloride at about 25° C. bythe general procedure of E. J. Corey et al., Tetrahedron Letters, 11,809-812 1976.

The following examples present typical syntheses as described in SchemeA. These examples are understood to be illustrative only and are notintended to limit the scope of the present invention in any way. As usedherein, the following terms have the indicated meanings: "g" refers tograms; "mmol" refers to millimoles; "mL" refers to milliliters; "bp"refers to boiling point; "mp" refers to melting point; "°C." refers todegrees Celsius; "mm Hg" refers to millimeters of mercury; "μL" refersto microliters; "μg" refers to micrograms; and "μM" refers tomicromolar.

EXAMPLE 1

4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,.alpha.-dimethylbenzeneaceticacid hydrochloride

METHOD A

Step a: 2,2-Dimethyl-phenethyl acetate

Dissolve α,α-dimethylphenyl acetic acid (140.0 g, 0.853mol) in anhydroustetrahydrofuran (100 mL) and place under a nitrogen atmosphere. Add, bydropwise addition, a solution of lithium aluminum hydride (639 mL of a1.0 M solution in tetrahydrofuran, 24.3 g, 0.639 mol) over a period ofapproximately 2 hours. Quench with deionized water (24 mL), with 15%aqueous sodium hydroxide (24 mL) and again with deionized water (72 mL).Stir the milky white mixture for 20 minutes, filter through filter aid,dry (MgSO₄) and filter through filter aid once more. Evaporate thesolvent in vacuo to give 2,2-dimethylphenethyl alcohol as a clear yellowoil.

Dissolve 2,2-dimethylphenethyl alcohol (118.0 g, 0.786 mol) in pyridine(700 mL). Add, by dropwise addition, acetic anhydride (222 mL, 240.7 g,2.358 mol) and stir overnight at room temperature. Evaporate the solventin vacuo and purify by distillation to give the title compound as aclear colorless oil; bp 75° C.@0.4 mmHg.

METHOD B

Dissolve 2-methyl-2-propenyl acetate (1.28 mmol) in benzene (80 mL) andadd to a stirred solution of AlCl₃ (172.3 g, 1.29 mol) in benzene (800mL) at -10° C. over 45 minutes under a stream of nitrogen. Stir at 5° C.for 20 minutes, pour onto ice (800 g) and stir for 10 minutes. Separatethe organic phase, dry (MgSO₄) and evaporate the solvent in vacuo (30°C./60 torr). Purify by distillation to give the title compound.

Step b: 4-(4--Chloro-1-oxobutyl)-2,2-dimethylphenethyl acetate

Charge a flask with aluminum chloride (223 g, 1.68 mol) and methylenechloride (200 mL). Place under a nitrogen atmosphere, cool to 0°-5° C.and add, by dropwise addition, ω-chlorobutyryl chloride (188.6 g, 1.34mol). After acid chloride addition is complete, add, by dropwiseaddition, 2,2-dimethylphenethyl acetate (128.0 g, 0.67 mol), keeping thetemperature at approximately 0° C. Continue stirring at 0° C. for 2hours, quench by slowly pouring over approximately 2 L of crushed ice.Add methylene chloride (500 mL) and stir for 5 minutes. Separate theorganic phase and extract the aqueous phase with methylene chloride (300mL). Combine the organic phases and wash with saturated aqueous sodiumhydrogen carbonate (3×200 mL), with deionized water (200 mL) and brine(200 mL). Dry (MgSO₄) and stir for 30 minutes before filtering.Evaporate the solvent in vacuo and purify by chromatography (ethylacetate/hexane) to give the title compound as an orange/brown oil.

IR (neat) 3239, 2970, 1741, 1684, 1607, 1408, 1375, 1233, 1040, 998,844, 823 cm⁻¹ ;

¹ H NMR (CDCl₃) δ 7.93 (d, 2H, J=9.0Hz), 7.46 (d, 2H, J=9.0 Hz), 4.14(s, 2H), 3.68 (t, 2H, J=7.5 Hz), 3.16 (t, E, J=7.5 Hz), 2.2 (m, 2H),2.00 (s, 3H), 1.38 (s, 6H);

¹³ C NMR (CDCl₃) δ 198.5, 170.9, 151.9, 134.8, 127.9, 126.2, 72.4, 44.6,38.6, 35.2, 26.7, 25.7, 20.8;

MS (CI, CH₄) m/z (rel. intensity) 297 (ME⁺, 56), 261 (59), 237 (100),219 (52).

Step c:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-2,2-dimethylphenethylalcohol

Mix 4-(4-chloro-1-oxobutyl)-2,2-dimethylphenethyl acetate (99.5 g, 0.335mol), α,α-diphenyl-4-piperidinemethanol (101.8 g, 0.335 mol), potassiumhydrogen carbonate (83.8 g, 0.838 mol), potassium iodide (1.00 g, 0.006mol), toluene (600 mL) and water (220 mL). Stir at reflux for 72 hours,add toluene (200 mL) and deionized water (100 mL). Filter through filteraid while at 80° C. and separate the organic phase. Dry (MgSO₄), filterand purify by chromatography (ethyl acetate) to give4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-2,2-dimethylphenethylacetate as an oily solid.

IR (KBr) 3690, 3608, 3012, 2950, 2810, 1734, 1681, 1607, 1470, 1448,1376, 1253, 1040, 997, 704, 667 cm⁻¹ ;

¹ H NMR (CDCl₃) δ 7.90 (d, 2H, J=8.2 Hz), 7.4 (m, 5H), 7.3 (m, 5H), 7.2(m, 2H), 4.14 (s, 2H), 3.0 (m, 4E), 2.4 (m, 3H), 2.0 (m, 3H), 1.95 (s,3H), 1.4 (m, 4H), 1.38 (s, 6H);

¹³ C NMR (CDCl₃) δ 199.4, 170.9, 151.7, 145.8, 135.1, 128.1, 128.0,126.5, 126.2, 125.7, 79.3, 72.5, 57.6, 53.7, 43.8, 38.6, 36.1, 25.7,21.2, 20.8;

MS (CI, CH₄) m/z (rel. intensity) 528 (ME⁺, 100), 510 (63), 450 (12),293 (14).

Dissolve4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-2,2-dimethylphenethylacetate (69.0 g, 0.131 mol) in methanol (2.5L) and add 10% aqueoussodium hydroxide (769 mL, 1.92 mol). Stir at reflux for 1.5 hours, coolto 68° C. and evaporate the solvent in vacuo to a residue (700 mL). Addchloroform (1 L) and stir until solids are dissolved. Separate theorganic phase and extract the aqueous phase with chloroform (3×300 mL).Combine the organic phases, dry (MgSO₄) and evaporate the solvent invacuo and recrystallize (toluene) to give the title compound as acream-colored powder; mp 135°-137° C.

IR (KBr) 3609, 3011, 2950, 2809, 2772, 1680, 1606, 1492, 1470, 1448,1366, 1282, 1238, 1044, 791, 704, 668 cm⁻¹ ;

¹ H NMR (CDCl₃) δ 7.93 (d, 2H, J=8.2 Hz), 7.4 (m, 5H), 7.3 (m, 5H), 7.2(m, 2H), 3.64 (s, 2H), 2.9 (m, 4H), 2.4 (m, 3H), 1.9 (M, 5H), 1.38 (s,6H), 1.3 (m, 4H);

¹³ C NMR (CDCl₃) δ 199.6, 152.1, 145.9, 135.2, 128.2, 126.4, 125.7,79.5, 72.7, 57.8, 53.9, 44.0, 40.4, 36.2, 26.1, 25.2, 22.2;

MS (CI, CH₄) m/z (rel. intensity) 486 (MH⁺, 100), 468 (81), 408 (19),293 (23).

Step d:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticacid hydrochloride

METHOD A

Dissolve oxalyl chloride (1.57 g, 12.4 mmol) in methylene chloride (17mL), cool to -55° C. and place under a nitrogen atmosphere. Add, bydropwise addition, a solution of dimethylsulfoxide (1.77 g, 1.61 mL) inmethylene chloride (4.5 mL). Stir for 15 minutes and add, by dropwiseaddition, a solution of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-2,2-dimethylphenethylalcohol (5.0 g, 10.3 mol) in methylene chloride (33 mL). Stir for 30minutes and add, by dropwise addition, triethylamine (7.2 mL). Stir for15 minutes and then allow to warm to -10° C. Add a solution of oxone(12.66 g) in deionized water (50 mL). Stir for 15 minutes and addmethylene chloride (25 mL). Separate the organic phase, wash with brine,dry (MgSO₄) and evaporate the solvent in vacuo. Purify by chromatography(ethyl acetate) to give4-[4-[4-(hydoxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetaldehyde.

¹ H NMR (CDCl₃) δ 9.52 (s, 1H), 7.95 (d, 2H, J =8.2 Hz), 7.5 (m, 4H),7.36 (d, 2H, J =8.2 Hz), 7.3 (m, 4H), 7.2 (m, 2H), 2.9 (m, 4H), 2.4 (m,4H), 2.0 (m, 4H), 1.50 (s, 6H), 1.4 (m, 4H);

¹³ C NMR (CDCl₃) δ 202, 199.9, 146.2, 136.2, 128.7, 128.3, 127.1, 126.6,125.9, 79.4, 57.7, 53.8, 50.6, 43.9, 42.5, 36.2, 25.9, 22.3, 21.5;

MS (CI, CH₄) m/z (tel. intensity) 484 (MH⁺, 76), 466 (100), 454 (19),406 (16), 293 (16), 233 (19), 183 (49, 155 (54).

Dissolve4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetaldehyde(3.40 g, 7.03 mmol) in acetone (30 mL) and cool to 15° C. Add, bydropwise addition, 1 N hydrochloric acid (10.5 mL). After addition ofthe hydrochloric acid is complete, add, by dropwise addition, a solutionof potassium permanganate (1.82 g, 11.51 mmol) in acetone (80 mL). Stirat room temperature for 6 hours, filter and wash the filter cake withacetone (60 mL). Evaporate the filtrate in vacuo, dilute with methylenechloride (500 mL), dry (MgSO₄) and filter. Evaporate the solvent invacuo and purify by chromatography (ethyl acetate) to give the titlecompound as a pale yellow solid.

IR (KBr) 3420, 3057, 2964, 1677, 1604, 1569, 1470, 1448, 1406, 1363,1249, 1189, 1099, 750, 705 cm⁻¹ ;

¹ H NMR (CDCl₃) δ 7.75 (d, 2H, J=8.2 Hz), 7.4 (m, 6H), 7.2 (m, 4H), 7.1(m, 2H), 3.9 (br. s, 2H), 3.1 (m, 2H), 2.9 (m, 2H), 2.6 (m, 2H), 2.3 (m,2H), 1.9 (m, 3H), 1.7 (m, 2H). 1.44 (s, 6H), 1.4 (m, 2H);

¹³ C NMR (CDCl₃) δ 199.4, 147.2, 134.5, 127.7, 127.5, 126.2, 125.7,78.4, 57.3, 53.5, 46.6, 43.5, 35.6, 26.8, 25.9, 21.3;

MS (CI, CH₄) m/z (rel. intensity) 500 (MH⁺, 79), 482 (62), 456 (100),422 (30), 366 (42).

METHOD B

Mix4-[4-[4-(hydoxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-2,2-dimethylphenethylalcohol (9.7 mmol), chloroform (20 mL), acetonitrile (20 mL), water (30mL) and H₅ IO₆ (5.6 g, 24.3 mmol). Add RuCl₃ •5H₂ O (0.15 g, 0.49 mmol)and stir at room temperature for 2 hours. Dilute the reaction mixturewith methylene chloride (200 mL), wash with saturated NaHSO₃ (2×100ML)and dry (MgSO₄). Filter, evaporate the filtrate in vacuo (20° C./60torr) and purify by silica gel chromatography to give the titlecompound.

METHOD C

Mix K₂ S₂ O₈ (2.8 g, 10.2 mmol), KOH (85%, 1.95 g, 30 mmol) and water(20 mL). Add RUCl₃ •5H₂ O (30mg, 0.2 mmol) and stir at room temperaturefor 5 minutes. Dissolve4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-2,2-dimethylphenethylalcohol (0.97 mmol) in acetone (14 mL) and acetonitrile (2 mL) and addto the above solution. Stir at room temperature for 2.5 hours, filterand neutralize the filtrate with 1 N HCl to pH 5. Extract with methylenechloride (2×50 mL), dry (MgSO₄), evaporate the solvent in vacuo (20°C./60 torr) and purify by silica gel chromatography to give the titlecompound.

METHOD D

Mix potassium permanganate (1.58 g, 10 mmol), water (4 mL) and aceticacid (26 mL). Cool to 5° C. and add phosporic acid (2.3 g of an 85%solution, 20 mmol). Stir vigorously and add, by dropwise addition, asolution of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]1-oxobutyl]-2,2-dimethylphenethylalcohol (970 mg, 2.0 mmol) in acetic acid (5 mL) over 5 minutes. Stir at5° C. for 2 hours, dilute with water (15 mL) and add Na₂ S₂ O₅ in smallportions until the solution becomes colorless. Remove most of the aceticacid and water under vacuum and partition the residue between water (15mL) and methylene chloride (60 ml). Separate the organic layer, washsequentially with water (2×30 mL) and dilute hydrochloric acid (10%, 20mL). Evaporate the solvent in vacuo to give the title compound as alight yellow foam (749 g, 70%).

MS (m/z) 500 (M+1); δ ¹ H NMR (DMSO-d₆) 7.79 (6H,m), 7.27 (4H, m), 7.14(4H, t), 3.02 (4H, m), 2.51 (2H, m), 2.22 (2H, t), 1.81 (2H, m), 1.60(3H, m), 1.44 (6H, s), 1.35 (2H, m).

Step e:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,.alpha.-dimethylbenzeneaceticacid hydrochloride

METHOD A

Add sodium borohydride (0.105 g, 2.77 mmol) to a solution of sodiumhydroxide (0.053 g, 1.33 mmol) in deionized water (2 mL) and add, bydropwise addition, to a solution of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (0.70 g, 1.31 mmol) in ethanol (30 mL). Stir at roomtemperature for 3.5 hours at pH 7-8. Evaporate the solvent in vacuo andstir the residue with methylene chloride (15 mL) and deionized water (15mL). Dry (MgSO₄), acidify to pH 3 with gaseous hydrogen chloride andevaporate the solvent. Add ether with stirring, filter the white solidand wash with additional ether. Dry to give the title compound.

IR (KBr) 3403, 3058, 2971, 1718, 1634, 1492, 1471, 1448, 1393, 1227,1150, 1099, 1069, 839, 750, 706 cm⁻¹ ;

¹ H NMR (CDCl₃) δ 7.50 (d, 4H, J=8.2 Hz), 7.3 (m, 8H), 7.2 (mr 2H), 4.66(t, 1H, J=5.6 Hz), 3.5 (m, 2H), 3.0 (m, 4H), 2.8 (m, 2H), 1.7 (m, 8H),1.53 (s, 6H);

¹³ C NMR (CDCl₃) δ 181.1, 147.4, 146.1, 144.4, 129.5, 128.0, 127.4,127.2, 79.9, 73.9, 57.0, 54.1, 42.7, 36.8, 27.1, 25.7, 21.7;

MS (CI, CH₄) m/z (rel. intensity) 502 (M H⁺, 50), 485 (33), 484 (100),458 (25), 454 (33), 424 (17).

Anal. Calcd for C₃₂ H₃₉ NO₄ •HCl•2.25H₂ O (7.0% Tg): C, 66.42; H, 7.75;N, 2.42;

Found: C, 65.68; H, 7.48; N, 2.32 (6.8% Tg).

METHOD B

Dissolve4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (2.0 g, 3.7 mmol) in ethanol (90 mL). Stir at roomtemperature for 10 minutes and add, by dropwise addition over 15minutes, sodium borohydride (0.3 g, 8 mmol) and a solution of sodiumhydroxide (0.16 g, 4 mmol) in water (5 mL). Stir for 30 minutes and coolin an ice-bath. Slowly add a solution made of concentrated hydrochloricacid (0.3 mL) and water (1 mL) to quench excess borohydride. Stir for 20minutes and evaporate the solvent in vacuo. Partition the residuebetween chloroform (50 mL) and water (35 mL), separate the organic phaseand extract the aqueous pase with chloroform (25 mL). Combine theorganic phases and wash sequentially with water (20 mL) and 15%hydrochloric acid (15 mL). Evaporate the solvent in vacuo and dissolvethe residue in methylene chloride (10 mL). Precipitate the product bydropwise addition of hexane and collect by filtration. Wash with hexaneand air dry to give the title compound as a light yellow powder (0.96 g,48%).

EXAMPLE 2

(R)-4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic,ethyl ester

Dissolve (+)-B-chlorodiisopinocamphenylborane (2.5 g, 7.8 mmol) inanhydrous tetrahydrofuran (5 mL). Add a solution of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic,ethyl ester (2 g, 3.54 mmol) in anhydrous tetrahydrofuran (5 mL). Stirat room temperature for 3 days and cool to 0° C. Add water (1 mL) and30% hydrogen peroxide (2 mL) and stir for 20 minutes. Add methylenechloride (30 mL) and wash with brine (30 mL), then aqueous sodiumhydrogen carbonate (30 mL), then brine (30 mL). Dry (MgSO₄), evaporatethe solvent in vacuo and purify by chromatography (1:19 methanol:ethylacetate) to give the title compound as a solid; mp 87°-90° C.

IR (KBr) 3436, 3058, 2932, 2813, 1725, 1632, 1599, 1470, 1448, 1255,1147, 1097, 830, 749, 704 cm⁻¹ ;

¹ H NMR (CDCl₃) δ 7.5 (m, 4H), 7.3 (m, 8H), 7.2 (m, 2H), 4.6 (m, 1H),4.08 (q, 2H, J =7.5 Hz), 3.1 (m, 1H), 3.0 (m, 1H), 2.4 (m, 3H), 2.0 (m,3H), 1.7 (m, 5H), 1.53 (s, 6H), 1.5 (m, 2H), 1.42 (s, 2H), 1.15 (t, 3H,J =7.5 Hz); [α]²⁰ _(D) +39.4° (c=0.99, CHCl₃).

EXAMPLE 3

(S)-4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid, ethyl ester

Dissolve (-)-B-chlorodiisopinocamphenylborane (2.5 g, 7.8 mmol) inanhydrous tetrahydrofuran (5 mL). Add a solution of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticacid, ethyl ester (2 g, 3.54 mmol) in anhydrous tetrahydrofuran (5 mL).Stir at room temperature for 3 days and cool to 0° C. Add water (1 mL)and 30% hydrogen peroxide (2 mL) and stir for 20 minutes. Add methylenechloride (30 mL) and wash with brine (30 mL), then aqueous sodiumhydrogen carbonate (30 mL), then brine (30 mL). Dry (MgSO₄), evaporatethe solvent and purify by chromatography to give the title compound.

What is claimed is:
 1. A process for preparing a compound of the formula##STR8## wherein R₁ represents hydrogen or hydroxy;R₂ representshydrogen; or R₁ and R₂ taken together form a second bond between thecarbon atoms bearing R₁ and R₂ ; n is an integer of from 1 to 5; R₃ is--CH₂ OH; A is hydrogen or hydroxy; and pharmaceutically acceptablesalts, hydrates and individual optical isomers thereof comprising thesteps of: (a) reacting a benzeneacetic acid compound of the formula##STR9## wherein A is as defined above and R is hydrogen or C₁ -C₆ alkylwith a suitable reducing agent to give a phenethyl alcohol; (b) reactingthe phenethyl alcohol with a ω-halo compound of the formula ##STR10##wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is asdefined above, in the presence of a suitable Lewis acid to produce aω-halo hydroxyethylphenylketone; (c) reacting the ω-halohydroxyethylphenylketone with a suitable reducing agent to produce aω-halo hydroxyethylphenylalcohol; (d) reacting the ω-halohydroxyethylphenylalcohol with a piperidine compound of the formula##STR11## wherein R₁ and R₂ are as defined above, in the presence of asuitable non-nucleophilic base to produce a piperidinehydroxyethylphenylalcohol; and (e) optionally reacting the piperidinehydroxyethylphenylalcohol with an appropriate deprotecting reagent,withthe proviso that each of the hydroxy groups present in the compoundsdescribed in steps a-d are optionally protected or unprotected.
 2. Aprocess according to claim 1 wherein the reducing agent of step c is(+)-B-chlorodiisopinocamphenylborane.
 3. A process according to claim 1wherein the reducing agent of step c is(-)-B-chlorodiisopinocamphenylborane.